A cross-sectional National Health and Nutrition Examination survey-based study of the association between systemic immune-inflammation index and blood urea nitrogen levels in United States adolescents

Blood urea nitrogen (BUN) level is one of the commonly used indicators to assess renal function and systemic immune-inflammatory status. In the adolescent population, changes in BUN levels may be associated with a variety of factors, including physiologic dehydration, lifestyle influences such as nutritional intake, physical activity, and possible endocrine or metabolic disorders. In recent years, more and more studies have shown that BUN levels are not only a reflection of kidney function, but it may also be related to the inflammatory state of the body. The Systemic Immune Inflammatory Index (SII) is a comprehensive index that takes into account platelet counts, neutrophil and lymphocyte counts, and is thought to be effective in reflecting the body's immune status and inflammatory response. However, research on the relationship between the two, SII and BUN, remains understudied in the adolescent population. The purpose of this study was to examine the relationship between SII and BUN levels in a population of American adolescents and to further analyze the factors that influence it. We conducted a cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES) database. Using descriptive statistics, correlation analysis, and regression analysis, we explored the relationship between SII and BUN levels. We found a significant negative correlation between SII and BUN levels, with BUN levels decreasing when SII levels increased (BUN as the dependent variable and SII as the outcome variable). We performed a multiple regression analysis of this relationship, controlling for possible confounders such as gender, age, race, and BMI, and found that this negative correlation remained significant. Our findings reveal an important relationship between SII and BUN levels and provide new perspectives for understanding adolescent health.


Study population and data sources
NHANES is a representative U.S. national population survey that uses complex, multistage, and probability sampling methods to provide a wealth of information about the nutrition and health of the general U.S. population 25 .
The Ethics Review Board of the National Center for Health Statistics (NCHS) approved the study protocol.Written informed consent was obtained from all survey participants or parents and/or guardians of individuals under 18 years of age.Visit https:// www.cdc.gov/ nchs/ nhanes/ index.htm for additional information.
Data from the NHANES 2009-2018 consecutive cycles (N = 49,693) were selected for this study to assess the relationship between BUN and SII among adolescents.First, adolescents and young adults were defined according to the World Health Organization's [26][27][28][29][30][31] .A total of 8646 eligible adolescents aged 10-19 years were included.We excluded participants with missing BUN values (N = 2997) and missing SII values (N = 384) from the eligible participants.The study ended up with 5,265 participants who met the inclusion criteria for subsequent analysis.A detailed flow chart of the participant nativity criteria is shown in Fig. 1.

Variables in research
Venous blood was drawn from participants, and serum samples were processed, stored, and then transported to a collaborative laboratory service department for analysis.The BUN was quantitatively determined using the enzyme conductance method (DxC800 biochemistry analyzer).The complete blood count was measured by professionally trained hematological researchers using an automatic hematology analyzer (Coulter DxH 800 analyzer).Subsequently, we conducted an analysis using lymphocyte, platelet, and neutrophil counts (expressed in thousands of cells/μL).Finally, SII (1000 cells/ul) was calculated as platelet count × neutrophil count/lymphocyte count as an exposure variable 32 .The NHANES Laboratory/Medical Technician Procedure Manual (LPM) details the collection and processing of specimens in exhaustive detail.
Other covariates included sex (male or female), race (Mexican American, other Hispanic, non-Hispanic black, non-Hispanic white, or other race) and education level (less than high school, or high school), and annual household income status.Continuous covariates included BMI (body mass index), RBC (red blood cells), HGB

Ethics statement
This study was reviewed and approved by the NCHS Ethics Review Board.The patients/participants provided their written informed consent to participate in The patients/participants provided their written informed consent to participate in this study.

Population-specific baseline data
Weighted baseline characteristics of the 5265 included participants (2188 males and 2170 females) based on SII quartiles are shown in Table 1.The mean age of the included participants was 15.45 ± 2.26 years, and the mean value of BUN was 10.99 ± 3.43 mg/dL.The ranges of SII quartiles 1-4 were < 285.42, 285.42-402.16,402.16-560.25, and ≥ 560.25.BUN levels were significantly higher in the highest quartile of SII index participants than in the lowest quartile of SII participants, and similarly, the number of people of different ages, genders, races, and educational levels was significantly higher in the highest quartile of SII index participants than in the lowest quartile of SII participants; Scr, HGB, ALT, AST, Scr, and HbA1c levels were all significantly lower than the lowest quartile of SII participants, but TG levels were significantly higher than the lowest quartile of SII participants (all P < 0.05).
Table 2 shows the relationship between BUN and SII.We found that the lower the BUN level, the higher the SII value in both the original and adjusted model 1.In the fully adjusted model it was found that for every unit decrease in BUN levels, SII increased by 2.29 units (β = − 2.29, 95% CI − 4.41, − 0.16).In addition, we further characterized an inverse relationship between BUN and and SII (P for trend = 0.1710).
Table 3 shows that in subgroup analyses stratified by gender, ethnicity, age group, and BMI, our results indicated that the negative association between BUN and SII was independently significant among US adolescents with a BMI ≥ 25.5 kg/m 2 [− 4.77 (− 8.24, − 1.30)], but was not statistically significant in all models with a BMI < 25.5 kg/m 2 .We performed smoothed curve fitting (Fig. 2) further in order to characterize the inverse relationship between BUN and SII.Using a two-stage linear regression model (Table 4), we found that stratified analyses by BMI revealed an inverse U-shaped curve for American adolescents with BMI < 25.5 kg/m 2 and BMI ≥ 25.5 kg/m 2 (Fig. 3), with an inflection point of 13 (mg/dL).

Discussion
The central finding of this study is that there is a significant negative correlation between SII and BUN levels in the US adolescent population.This means that as SII increases, indicating increased inflammation and immune activity, BUN levels show a downward trend.This result not only reveals the potential importance of SII and BUN levels in adolescent health monitoring, but also highlights the complex interactions between the immune system and metabolic processes during adolescence.
First, elevated SII usually reflects the body's response to inflammation [33][34][35][36] .In adolescence, this response may be more complex, as the immune system is rapidly developing and adjusting [37][38][39] .For example, one study demonstrated differences in immune cell ratios and activity in adolescence compared to adults, which may influence levels of inflammatory markers 40 .Second, the decrease in BUN levels may reflect specific changes in body and kidney function in inflammatory states 41,42 , and in certain pathological states, such as severe inflammation or infection, the body may respond to external stresses by altering metabolic pathways, such as by increasing protein synthesis and decreasing catabolism, which may similarly affect BUN levels.Also, even in the presence of impaired renal function, the kidneys may partially compensate for decreased excretion of urea by increasing the excretion of other metabolic wastes (e.g., creatinine).In addition, the kidneys may regulate BUN levels by altering urea reabsorption, especially in mild or moderate renal insufficiency.This is particularly critical in the adolescent population, as they are at a critical stage of growth and development.The kidneys, as the main organs of metabolism and excretion, are particularly sensitive to hormonal changes 43 .It has been suggested that hormonal fluctuations during adolescence may affect renal function and regulation 44 .During the rapid growth phase of adolescence, the metabolic activity of an organism tends to support the establishment and development of new tissues, which typically requires more anabolic processes to meet the demands of growth.As a result, the breakdown of proteins and other key nutrients may be reduced, which helps to explain why BUN levels may be lower during this growth phase, as the primary source of urea is the breakdown of proteins.Notably, this study found that the relationship between SII and BUN remained significant even after controlling for age, gender, race, and BMI.This finding suggests that the association between SII and BUN may be driven by deeper physiological processes 8 .For example, gender differences may influence immune responses and metabolic processes in adolescents [45][46][47] .One study showed significant differences in immune response between adolescent females and males, which may influence their inflammatory markers 48 .In addition, the influence of lifestyle factors, such as diet and exercise, on SII and BUN cannot be ignored.In adolescents, the occurrence of dehydration may be closely related to lifestyle (e.g., physical activity, drinking habits, etc.) due to physiological and behavioral peculiarities.Dehydration leads to a decrease in body water, which increases blood viscosity and plasma osmolality.This change stimulates the kidneys to conserve water by decreasing the volume of urine, which in turn leads to higher blood urea nitrogen (BUN) concentrations.In adolescence, when renal function and metabolic status may be more active or unstable due to growth and development, dehydration may lead to more pronounced changes in these indicators.At the same time, dehydration may affect the counts and ratios of these cells, including platelets, neutrophils, and lymphocytes, through several mechanisms.First, hemoconcentration due to dehydration can artificially increase cell counts in the blood, including neutrophils and platelets, which may lead to elevated SII.Second, prolonged or severe dehydration may affect the body's www.nature.com/scientificreports/immune response by affecting the cellular function and survival environment, which in turn may affect the body's immune response 49,50 .
Several studies have noted that SII tends to be elevated and positively correlated with BUN levels in chronic disease states such as chronic kidney disease or cardiovascular disease 24,51 , whereas our study observed a negative correlation between SII and BUN in a generally healthy group of adolescents.This difference may stem from the different health states of the sample groups.In chronic disease states, the inflammatory response may be more pronounced, thus affecting renal function and leading to elevated BUN.In healthy adolescents, on the other hand, lower SII may reflect lower levels of inflammation and normal renal function, so BUN is maintained at a lower level.Secondly, some studies have found that SII and BUN may be positively correlated in metabolic abnormalities conditions such as metabolic syndrome 52 , which again differs from our findings.This may be due to the fact that inflammation and metabolic abnormalities in patients with metabolic syndrome may lead to impaired renal function, which in turn affects BUN levels.In the general population of adolescents, this relationship is less pronounced due to the lack of significant metabolic disease burden.
Overall, this study emphasizes the importance of focusing on SII and BUN levels in adolescent health surveillance.It is hoped that it will provide new perspectives on adolescent health management and disease prevention, and provide a more solid foundation for further subsequent studies.Of course there are some limitations and shortcomings in our study.First, our data were obtained from the NHANES database, and although this is a nationally representative health and nutrition survey data, its data quality and reliability still need to be further verified.Second, because of the cross-sectional design of this study, we were only able to observe a correlation between SII and BUN, and could not determine whether, and what kind of causal relationship existed between them.Future studies should adopt a longitudinal study design to track individual changes over time in order to reveal causality more accurately.Finally, our sample may not have fully covered adolescents of different ethnic and socioeconomic backgrounds, which may affect the generalizability of the findings.Future studies should include a wider range of population groups to ensure broad applicability and validity of the results.Finally, our research model did not encompass the effects of factors such as diet, exercise, and sleep on SII and BUN, and future studies should include detailed information on these variables to more fully understand their relationship with SII and BUN.
In response to the limitations mentioned above, for future studies, we consider that improvements can be made in the following ways: First, in order to determine if, and what kind of causal relationship exists between SII and BUN, future studies should utilize a longitudinal research design.Second, expanding the diversity of the sample to include adolescents from different ethnic and socioeconomic backgrounds will ensure broader representation and applicability of the findings.This can be accomplished by collaborating multiple different districts for multi-center sample collection.Further, laboratory studies can be conducted to explore the interactions between immune response, metabolic regulation, and hormonal regulation at the molecular level.This can be accomplished through biochemical analysis of biological samples such as blood and urine.Finally, adolescentspecific intervention studies, such as diet and exercise programs, could be designed and implemented to assess how these interventions affect SII and BUN levels, thereby providing more specific recommendations for health improvement.With these improvements, future studies will not only overcome the limitations of existing studies, but also provide a more in-depth and comprehensive scientific basis for adolescent health surveillance and disease prevention.

Conclusion
Overall, this study revealed a significant negative correlation between BUN levels and SII in a population of US adolescents and found that this association showed variability among adolescents with different BMIs.This finding has key implications for a deeper understanding of metabolic and immune functions during adolescence and provides new research directions for future studies in related areas.Future studies should aim to investigate the biological mechanisms behind this relationship and its possible impact on adolescent health.

Table 1 .
Baseline characteristics of the study population according to SII stratification.SII systemic immune-inflammation index, BMI body mass index, RBC red blood cell, HGB hemoglobin, AST aspartate aminotransferase, ALT alanine aminotransferase, BUN blood urea nitrogen, TC total cholesterol, SCR serum creatinine, GLU serum glucose, SUA serum uric acid, HbA1c glycosylated hemoglobin, TG triglycerides, a Weighted means ± SD for continuous variables; weighted proportions for categorical variables.

Table 4 .
Threshold effect analyses of BUN and SII in U.S. adolescents with different BMI.